Aging is the strongest predictor for the development of cardiovascular disease. Peripheral arterial disease (PAD) is a common and debilitating form of cardiovascular disease characterized by atherosclerotic lesions in the large and medium sized arteries of the legs. Data from 2015 suggest that > 200 million people worldwide have PAD; PAD is prevalent in 7% of people age 55-59 and in 20% of people age 80-84. More than $4.4 billion is spent on PAD each year in the United States. PAD is associated with pain during walking (i.e., ?intermittent claudication?), decreased functional independence, and an extremely high risk of coronary heart disease and cardiac death. Stated another way, patients with stage I or stage II PAD (also called ?claudication?) visit their doctor because they have leg pain, but coronary disease is what will most likely kill them. Therefore, effective strategies that improve walking ability and coronary vascular health in PAD patients are needed. In this R21 application we propose mechanistic-driven intervention studies to improve a disease that is highly prevalent in the geriatric population. We will use a T1 translational approach. Specifically, we are applying basic and clinical findings toward new strategies to improve walking ability and coronary vascular function in human subjects with diagnosed PAD. In Aim 1, we will evaluate the effect of acute cardioselective ?1 blockade (with esmolol) on coronary blood flow, calf muscle oxygenation, and systemic BP during exercise in PAD. In Aim 2, we will evaluate the effect of four to six days of dietary nitrate supplementation (beetroot juice) on coronary blood flow, calf muscle oxygenation, and systemic BP during exercise in PAD. There is a strong scientific premise to conduct the proposed studies. Despite the prevalence of PAD and the associated poor coronary outcomes, only our recently published study (Ross et al 2017) has measured coronary blood flow during exercise in PAD patients. Moreover, the single study that evaluated the effects of dietary nitrate supplementation on walking performance and peripheral vascular responses in PAD was underpowered and did not use a true placebo. In this T1 translational project, we will fill these gaps in knowledge by conducting rigorously designed, mechanism-driven intervention studies in older adults (55-85 yr) with symptomatic PAD. If these exploratory studies identify ?1-blockade and/or dietary nitrate as safe and efficacious for PAD, our team of investigators will be well positioned to conduct a multi-center study (which would be needed to ultimately change the standard of care in these patients).